This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Influenza represents one of the most serious and common pandemic/epidemic viral diseases of human populations. Rapid mutations and rearrangements of the viral genome allow the virus to evade host immune responses, making the frequent development of vaccines to new viral variants necessary. We have developed a new approach to immunization for influenza that combines a unilamellar liposome carrier with a recombinant protein expressing specific antigenic epitopes. The recombinant protein immunogen incorporates a conserved N-terminal sequence of the structural M2 protein prospectively constructed to represent a variety of influenza H and N subtypes. The antigenic component of the protein is fused to a water-soluble hydrophobic protein domain that facilitates efficient integration of the antigen to lipid bilayer membranes. The water solubility properties of the hydrophobic fusion protein allows for its isolation and purification using commercially viable preparative procedures. We have previously shown that a M2e-based influenza vaccine (L-IAVM2e1-HD) stimulates active protective responses in mice and the objective of our present proposal is to confirm that the L-IAVM2e1-HD vaccine will provide similar protective immunity in ferrets and non-human primates. Comparative evaluation of the L-IAVM2e1-HD vaccine in ferrets and non-human primates are important studies because: 1) the ferret is a widely accepted model for testing of influenza vaccine candidates prior to clinical testing and;2) the correlates of protective immunity are unknown for M2-based vaccines in higher animals and thus, the establishment of surrogate endpoints for monitoring protective immune responses will be essential for setting the criteria for clinical testing of other M2 vaccine candidates where evaluation of efficacy, i.e., as in the case of an avian influenza vaccine, will not be possible. We believe that testing of the LIAVM2e1- HD vaccine will demonstrate that it is a highly effective means of stimulating protective responses against a structural, conserved viral protein, thereby facilitating the development of a vaccine against influenza that would not be rendered ineffective by antigenic shifts and/or drifts associated with mutations of the influenza H and N surface proteins. Vaccines based upon recombinant protein technologies also offer the opportunity to rapidly and efficiently adjust to changes in the virus, either natural or man-made, to generate new vaccines as needed. Taken together, the attractive features of this vaccine technology are designed to provide a major improvement in our ability to respond to influenza infections and the potential use of influenza as a biological weapon.